In previous studies, we have identified human regulatory T cells that are stimulated by self MHC class molecules harboring self-peptides. These cells were found to produce IL-10 and TGF-beta under various conditions and to suppress immune function via the secretion of this cytokine. Studies of the occurrence of these cells in patients with SLE and their role in SLE pathogenesis is on-going. In the present studies we have widened these studies to include CD25+ regulatory cells which arise in the thymus and suppress T cells via cell-cell interaction. Here we demonstrated that murine CD4+CD25+ T cells produce high levels of transforming growth factor-beta1 (TGF-beta1) and interleukin-10 (IL-10) compared with CD4+CD25- T cells when stimulated by plate-bound anti-CD3 and soluble anti-CD28 and/or IL-2, and secretion of TGF-beta1 (but not other cytokines), is further enhanced by costimulating via cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Thus, in their suppressor cytokine secretion pattern CD25+ T cells are similar in many respects to self-MHC reactive T cells. In further studies, we found that murine resting CD25+ T cells (but not CD25- T cells) express substantial amounts of surface TGF-beta1 in the form of "latent" TGF-beta, i.e., TGF-beta associated with latency-associated protein. Furthermore, such surface expression is greatly increased following activation with anti-CD3 presented by APC's in the presence of IL-2, i.e., conditions not associated with TGF-beta secretion. In a final series of studies of murine CD25+ T cells we studied their capacity to suppress immune respones and found that under stimulation conditions resulting in surface TGF-beta expression but not TGF-beta secretion CD25+ T cells suppressed both CD25- T cell (proliferation)responses to helper activity for B cell (Ig production) responses in cultures allowing cell-cell contact and that such suppression is reversed by addition of anti-TGF-beta. These data strongly suggest that CD25+ T cells play a dual regulatory role: under maximal stimulation conditions they secrete TGF-beta (and IL-10) and act as self-MHC-reactive suppressor T cells (or Th3 T cells); in contrast, under minimum stimulation conditions that act via cell-cell contact to suppress T cell response. In the latter instance, it is presumed but not proven that the latent TGF-beta is activated at the cell surface. Recently, we have extended these studies to humans and have been able to show that circulating CD4+ T cells also express latent TGF-beta.